HEAR-MHE study: Automated speech analysis identifies minimal hepatic encephalopathy and may predict future overt hepatic encephalopathy.

BACKGROUND AIMS: Hepatic encephalopathy (HE) is a major cause of poor quality of life in patients with cirrhosis. A simple diagnostic test to identify minimal HE (MHE) and predict future overt HE (OHE) is lacking. We aimed to evaluate if analysis of speech patterns using a modern speech platform: 1) correlates with validated HE tests, 2) correlates with MHE, and 3) predicts future OHE. APPROACH RESULTS: In a two-center prospective cohort study of 200 outpatients with cirrhosis and 50 controls, patients underwent baseline speech recording and validated HE diagnostic testing with psychometric HE score (PHES). Patients were followed for 6 months to identify episodes of OHE. 752 speech variables were extracted using an automated speech analysis platform, reflecting the acoustic, lexical, and semantic aspects of speech. Patients with cirrhosis were median 63 years old (IQR 54, 68), 49.5% (99) were female. Over 100 speech variables were significantly associated with PHES (p <0.05 with FDR adjustment). A three-variable speech model (two acoustic, one speech tempo variable) was similar to animal naming test in predicting MHE (AUC 0.76 vs. 0.69; p=0.11). Adding age and MELD-Na improved accuracy of the speech model (AUC: 0.82). A combined clinical-speech model ("HEAR-MHE model") predicted time to OHE with a concordance of 0.74 (p=0.06). CONCLUSIONS: Automated speech analysis highly correlated with validated HE tests, associated with MHE, and may predict future OHE. Future research is needed to validate this tool and to understand how it can be implemented in clinical practice.

Noninvasive liver disease assessment to identify portal hypertension: Systematic and narrative reviews supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. HVPG, a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and availability, noninvasive liver disease assessments to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. APPROACH AND RESULTS: We conducted a systematic review of Ovid MEDLINE(R) Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database's inception to April 22, 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies, which compared noninvasive tests (blood and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥ 10 mm Hg) in patients with chronic liver disease. Outcomes included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. Nine studies with 2492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood-based tests, including aspartate-to-platelet ratio index (APRI) (56% sensitivity and 68% specificity) and FIB-4 (54% sensitivity and 73% specificity) had low accuracy measures. Imaging-based tests (transient elastography and shear wave elastography detection of liver stiffness measurement [LSM]) had better accuracy but also had substantial variation; at 15 kPa, TE sensitivity was 90%-96% and specificity was 48%-50%, while at 25 kPa, its sensitivity and specificity were 57%-85% and 82%-93%, respectively. The narrative review suggested that imaging-based tests are the best available noninvasive liver disease assessment to detect CSPH; CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. CONCLUSIONS: While imaging-based noninvasive liver disease assessment appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the systematic review. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

HES V2.0 outperforms GALAD for detection of HCC: A phase 3 biomarker study in the United States.

BACKGROUND AND AIMS: The original hepatocellular carcinoma early detection screening (HES) score, which combines alpha-fetoprotein (AFP) with age, alanine aminotransferase, and platelets, has better performance than AFP alone for early HCC detection. We have developed HES V2.0 by adding AFP-L3 and des-gamma-carboxy prothrombin to the score and compared its performance to GALAD and ASAP scores among patients with cirrhosis. APPROACH AND RESULTS: We conducted a prospective-specimen collection, retrospective-blinded-evaluation phase 3 biomarker cohort study in patients with cirrhosis enrolled in imaging and AFP surveillance. True-positive rate (TPR)/sensitivity and false-positive rate for any or early HCC were calculated for GALAD, ASAP, and HES V2.0 scores within 6, 12, and 24 months of HCC diagnosis. We calculated the AUROC curve and estimated TPR based on an optimal threshold at a fixed false-positive rate of 10%. We analyzed 2331 patients, of whom 125 developed HCC (71% in the early stages). For any HCC, HES V2.0 had higher TPR than GALAD overall (+7.2%), at 6 months (+3.6%), at 12 months (+7.2%), and 24 months (+13.0%) before HCC diagnosis. HES V2.0 had higher TPR than ASAP for all time points (+5.9% to +12.0%). For early HCC, HES V2.0 had higher sensitivity/TPR than GALAD overall (+6.7%), at 12 months (+6.3%), and 24 months (+14.6%) but not at 6 months (+0.0%) and higher than ASAP for all time points (+13.4% to +18.0%). CONCLUSIONS: In a prospective cohort study, HES V2.0 had a significantly higher performance for identifying new HCC, including early stage, than GALAD or ASAP.

Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. APPROACH AND RESULTS: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR-) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86, respectively; LR+ and LR- for NAFLD F2-4, F3-4, and F4 were 2.65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. CONCLUSIONS: Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.

Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Serum biomarker signature is predictive of the risk of hepatocellular cancer in patients with cirrhosis.

BACKGROUND: Inflammatory and metabolic biomarkers have been associated with hepatocellular cancer (HCC) risk in phases I and II biomarker studies. We developed and internally validated a robust metabolic biomarker panel predictive of HCC in a longitudinal phase III study. METHODS: We used data and banked serum from a prospective cohort of 2266 adult patients with cirrhosis who were followed until the development of HCC (n=126). We custom designed a FirePlex immunoassay to measure baseline serum levels of 39 biomarkers and established a set of biomarkers with the highest discriminatory ability for HCC. We performed bootstrapping to evaluate the predictive performance using C-index and time-dependent area under the receiver operating characteristic curve (AUROC). We quantified the incremental predictive value of the biomarker panel when added to previously validated clinical models. RESULTS: We identified a nine-biomarker panel (P9) with a C-index of 0.67 (95% CI 0.66 to 0.67), including insulin growth factor-1, interleukin-10, transforming growth factor ß1, adipsin, fetuin-A, interleukin-1 ß, macrophage stimulating protein α chain, serum amyloid A and TNF-α. Adding P9 to our clinical model with 10 factors including AFP improved AUROC at 1 and 2 years by 4.8% and 2.7%, respectively. Adding P9 to aMAP score improved AUROC at 1 and 2 years by 14.2% and 7.6%, respectively. Adding AFP L-3 or DCP did not change the predictive ability of the P9 model. CONCLUSIONS: We identified a panel of nine serum biomarkers that is independently associated with developing HCC in cirrhosis and that improved the predictive ability of risk stratification models containing clinical factors.

Donor and recipient genetics: Implications for the development of posttransplant diabetes mellitus.

Posttransplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. One thousand one hundred fifteen liver transplant recipients without a pretransplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from 2 transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR [95% CI] = 3.79 [1.10-13.1], P = .035). Recipient risk was linked to factors associated with insulin secretion (OR [95% CI] = 0.85 [0.74-0.98], P = .02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR [95% CI] = 0.86 [0.75-0.99], P = .03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity.

The current landscape of in situ and ex-situ machine perfusion utilization for liver grafts from cardiac donation after circulatory death donors in the US.

Donation after circulatory death (DCD) is driving the increase in deceased organ donors in the United States. Normothermic regional perfusion (NRP) and ex-situ machine perfusion (es-MP) have been instrumental in improving liver transplant outcomes and graft utilization. This study examines the current landscape of liver utilization from cardiac DCD donors in the US. Using the UNOS STAR file, all adult (≥ 18 years old) DCD donors in the US in which the heart was used for transplantation from October 1, 2020, to September 30, 2023, were compared using procurement technique (NRP versus super rapid recovery [SRR]) and storage strategy (es-MP versus static cold storage [SCS]). 188 livers were transplanted from 309 TA-NRP donors (61% utilization) versus 305 (56%) liver transplants from 544 SRR donors. Es-MP was used in 20% (n= 38) of NRP cases versus 32% (98) of SRR cases. 281 (59%) of liver grafts were exposed to NRP, es-MP, or both. While there is widespread utilization of machine perfusion, more research is needed to determine optimal graft management strategies, particularly concerning the use of multiple technologies in complementary ways. More complete data collection is necessary at a national level to address these important research questions.

Variation in intention-to-treat survival by MELD subtypes: all models created for end-stage liver disease are not equal.

BACKGROUND & AIMS: Kidney dysfunction is a major determinant of prognosis in patients with decompensated cirrhosis awaiting transplantation. We hypothesized that for identical MELD scores at listing, outcomes before and after liver transplantation may vary if the predominant driver of the MELD score is serum creatinine versus serum bilirubin or INR. METHODS: We evaluated all adult patients registered for liver transplantation (LT) between 2016 - 2020 and excluded patients receiving MELD exceptions or undergoing dual organ transplantation. Using K-Means clustering analysis, we classified each patient as MELD-Br, MELD-INR or MELD-Cr depending on the dominant variable for their MELD score. The primary outcome was intent-to-treat survival, defined as survival within 1 year from listing with or without LT. RESULTS: MELD scores of LT waitlist registrants clustered into 3 subtypes: MELD-Br (n=13,658), MELD-INR (n=13,809), and MELD-Cr (n=12,412). One-year ITT survival was 78% (MELD-Br), 75% (MELD-INR), and 65% (MELD-Cr), p<0.01. ITT survival was lower for each MELD subtype for females compared to males (e.g. MELD Cr 63% females vs 67% males, p<0.0001). MELD-Cr subtype had the highest MELD at listing (MELD Cr 23.4 vs MELD-Br 19.2 vs MELD INR 21.0) and the largest decline in MELD over 3 months (23% vs. 12% vs 21%). In adjusted analyses including MELD Na, MELD-Cr compared to the other subtypes was associated with higher WL mortality (HR 1.339, 95% CI 1.279-1.402) and lower LT rates (HR 0.688, 95% CI 0.664-0.713). CONCLUSIONS: For equivalent listing practices, registrants with MELD-Cr subtype have lower ITT survival. MELD subtype may serve as a more sophisticated variable for dynamic assessment of risk of mortality, to inform models for organ allocation. IMPACT AND IMPLICATIONS: The MELD score is an excellent predictor of waitlist mortality; however, our work highlights that the driver of a patient's score MELD score matters and particularly those driven by elevated creatinine have a lower 1-year ITT mortality. The 1-year ITT mortality is also lower for women compared to men within the Cr-dominant subtype. These results are important for physicians and patients undergoing LT evaluation as creatinine may serve as a marker of prognosis and even if the creatinine improves the prognosis remains poor, necessitating discussion about alternative pathways for transplant. Our work also highlights that the type of kidney injury matters, in that those AKI were more likely to die or remain on the waitlist compared to those with CKD within the creatinine dominant subtype.

Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

PNPLA3, Obesity, and Heavy Alcohol Use in Cirrhosis Patients May Exert a Synergistic Increase Hepatocellular Carcinoma Risk.

BACKGROUND & AIMS: In patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors. METHODS: We analyzed data from 1911 patients in 2 multicenter prospective cohort studies in the United States. We classified patients according to alcohol consumption (current heavy vs not current heavy), obesity (body mass index ≥30 vs <30 kg/m2), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs noncarrier). We examined the independent and joint effects of these risk factors on risk of developing HCC using Cox regression with competing risks. RESULTS: Mean age was 59.6 years, 64.3% were male, 28.7% were Hispanic, 18.3% were non-Hispanic Black, 50.9% were obese, 6.2% had current heavy alcohol consumption, and 58.4% harbored at least 1 PNPLA3 G-allele. One hundred sixteen patients developed HCC. Compared with PNPLA3 noncarriers without heavy alcohol consumption, HCC risk was 2.65-fold higher (hazard ratio [HR], 2.65; 95% confidence interval [CI], 1.20-5.86) for carriers who had current heavy alcohol consumption. Compared with noncarrier patients without obesity, HCC risk was higher (HR, 2.40; 95% CI, 1.33-4.31) for carrier patients who were obese. PNPLA3 and alcohol consumption effect was stronger among patients with viral etiology of cirrhosis (HR, 3.42; 95% CI, 1.31-8.90). PNPLA3 improved 1-year risk prediction for HCC when added to a clinical risk model. CONCLUSIONS: The PNPLA3 variant may help refine risk stratification for HCC in patients with cirrhosis with heavy alcohol consumption or obesity who may need specific preventive measures.

Improvement in Survival After Transplantation for Critically Ill Patients With Cirrhosis in the United States.

INTRODUCTION: There is considerable debate over the indication of liver transplantation (LT) for critically ill patients with cirrhosis, in part due to their potentially poor post-LT prognosis. We analyzed the epidemiology and outcome of LT for critically ill patients with cirrhosis over 4 time periods of 4 years. METHODS: We included adult patients who underwent liver transplant alone between 2005 and 2020 using the United Network for Organ Sharing registry database. We defined critically ill patients with cirrhosis as being in the intensive care unit with 1 or more of the following characteristics at the time of LT: (i) grade III/IV hepatic encephalopathy, (ii) mechanical ventilation, (iii) dialysis, and (iv) vasopressors. RESULTS: A total of 85,594 LT recipients were included, 5,827 (6.8%) of whom were classified as being critically ill with cirrhosis at the time of LT. The number and percentage of critically ill LT recipients with cirrhosis increased over the study period: 819 (4.3%) in 2005-2008 vs 2,067 (7.9%) in 2017-2020, P < 0.001. There was a 17% absolute increase in 1-year survival after LT: 72.5% in 2005-2008 vs 89.5% in 2017-2020, P < 0.001. The 1-year post-LT survival gap between critically ill and noncritically ill patients with cirrhosis narrowed over the study period: 16.7 percentage points in 2005-2008 vs 4.6 percentage points in 2017-2020. The year of LT was independently associated with lower 1-year post-LT mortality (hazard ratio 0.92, 95% confidence interval 0.91-0.93, P < 0.001). DISCUSSION: The absolute number and relative percentage of LT recipients who were critically ill increased over time, as did 1-year post-LT survival. Meanwhile, the gap in survival between this group of patients and noncritically ill patients with cirrhosis decreased but persisted. Cautious access to selected LT candidates who are critically ill may be warranted, provided the gap in survival with noncritically ill patients remains as small as possible.

Predictors of Respiratory Failure Development in a Multicenter Cohort of Inpatients With Cirrhosis.

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.

Performance of race-neutral eGFR equations in patients with decompensated cirrhosis.

The 2021 Chronic Kidney Disease Epidemiology Collaboration equation [CKD-EPI 2021] is a race-neutral equation recently developed and rapidly implemented as a reference standard to estimate glomerular filtration rate(GFR). However, its role in cirrhosis has not been examined especially in low GFR. We analyzed the performance of CKD-EPI 2021 compared to other equations with protocol-measured GFR (mGFR) in cirrhosis. We analyzed 2090 unique adult patients with cirrhosis undergoing protocol GFR measurements using iothalamate clearance from 1985 to 2015 when listed for liver transplantation at Baylor University in Dallas and Fort Worth, Texas. Using mGFR as a reference standard, the CKD-EPI 2021 was compared to CKD-EPI 2012, Modification of Diet in Renal Disease-4, Modification of Diet in Renal Disease-6, Royal Free Hospital, and GFR Assessment in Liver disease overall and in certain subgroups (ascites, mGFR ≤ 30 mL/min/1.73 m 2 , diagnosis, Model for End-Stage Liver Disease and gender). We examined bias (difference between eGFR and mGFR), accuracy (p30: eGFR within ± 30% of mGFR) and agreement between eGFR and mGFR categories. CKD-EPI 2021 had the second lowest bias across the entire range of GFR after GFR Assessment in Liver disease (6.6 vs. 4.6 mL/min/1.73 m 2 , respectively, p < 0.001). The accuracy of CKD-EPI 2021 was similar to CKD-EPI 2012 (p30 = 67.8% vs. 67.9%, respectively) which was higher than the other equations ( p < 0.001). It had a similar performance in patients with ascites, by diagnoses, Model for End-Stage Liver Disease subgroups, by gender, and in non-Black patients. However, it had a relatively higher overestimation in mGFR ≤ 30 mL/min/1.73 m 2 than most equations (18.5 mL/min/1.73m 2 , p < 0.001). Specifically, 64% of patients with mGFR ≤ 30 mL/min/1.73m 2 were incorrectly classified as a less severe CKD stage by CKD-EPI 2021. In Blacks, CKD-EPI 2021 underestimated eGFR by 17.9 mL/min/1.73 m 2 , which was higher than the alternate equations except for Royal Free Hospital ( p < 0.001). The novel race-neutral eGFR equation, CKD-EPI 2021, improves the GFR estimation overall but may not accurately capture true kidney function in cirrhosis, specifically at low GFR. There is an urgent need for a race-neutral equation in liver disease reflecting the complexity of kidney function physiology unique to cirrhosis, given implications for organ allocation and dual organ transplant.

The rising cost of liver transplantation in the United States.

Liver transplantation (LT) is the only curative treatment for end-stage liver disease and significantly improves patient outcomes. However, LT is resource-intensive and costly, with expenditures rising dramatically in recent years. Factors contributing to this increase in cost include expanded transplant criteria, utilization of marginal organs, and broader organ distribution, resulting in significant logistical expenses. Advanced technologies like organ perfusion devices, while promising better outcomes, further inflate costs due to their high price and market monopolization. Moreover, living donor liver transplant (LDLT) and utilization of donation after cardiac death (DCD) organs introduce higher initial expenditures yet potential long-term savings. Despite rising costs, reimbursement has remained largely stagnant, putting financial strain on transplant programs, and threatening their sustainability. This review examines the multifaceted drivers of rising costs in LT, focusing on recent policy changes, the role of organ procurement organizations (OPOs) and the impact of new technologies. We also propose comprehensive solutions at national, OPO, and local levels, including optimizing resource allocation, leveraging regional collaborations, and advocating for revised reimbursement models to curb escalating costs. Addressing these challenges is critical to ensuring the continued viability of LT programs and maintaining patient access to this life-saving intervention.

Prospective evaluation of cystatin C in the assessment of kidney dysfunction and survival in liver transplant candidates.

Kidney dysfunction is associated with decreased survival in liver transplant (LT) candidates, yet serum creatinine (sCr) is a poor surrogate for glomerular filtration rate (GFR) in this population. Serum cystatin C (CysC) may provide a more accurate assessment of kidney function and predict outcomes. We performed a multicenter prospective cohort study of consecutive LT candidates. CysC was obtained at LT evaluation (n=244) and a subset underwent simultaneous I125-iothalamate clearance for measured GFR (mGFR) assessment (n=137). Patients were followed to assess need for pre-LT renal replacement therapy (RRT), simultaneous liver-kidney transplant (SLKT), and survival. Estimated GFR (eGFR) based on MDRD-4, GRAIL, Royal Free Hospital Cirrhosis GFR, and the CKD-EPI equations was assessed for bias, precision, and accuracy in reference to mGFR. Receiver operator characteristic (AUROC) and competing risks survival analyses were performed. CysC more accurately discriminated mGFR than sCr at thresholds of ≤60 mL/min/1.73 m2 and ≤30 mL/min/1.73 m2 with AUROC 0.92 (p=0.005) and 0.96 (p=0.01), respectively. All eGFR equations overestimated GFR, especially among females (p<0.05). The GRAIL equation demonstrated the least bias, while CKD-EPI-cystatin C was associated with the greatest precision and lowest frequency of GFR overestimation. Among 165 LT recipients, CysC discriminated pre-LT renal replacement therapy and the need for simultaneous liver-kidney transplant with AUROC of 0.70 and 0.85, respectively. Cumulative incidence of death, accounting for LT as a competing event, increased with CysC (p=0.002) but was not observed with sCr overall or among subgroups (p=NS). CysC more accurately predicts thresholds of mGFR than sCr in LT candidates. Elevated CysC discriminates pre-LT RRT and SLKT, and is strongly associated with survival in contrast with sCr. CysC is a promising tool to improve prognostication among LT candidates.

Controversies in terlipressin and transplantation in the United States: How do we MELD the two?

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a severe complication of cirrhosis that carries a poor prognosis. The recent Food and Drug Administration approval of terlipressin has substantial implications for managing HRS-AKI and liver allocation in the United States. Terlipressin has been available in Europe for over a decade, and several countries have adapted policy changes such as Model for End-Stage Liver Disease (MELD) score "lock" for HRS-AKI. In this article, we outline the European experience with terlipressin use and explore the question of whether terlipressin treatment for HRS-AKI should qualify for the MELD score "lock" in the United States in those who respond to therapy. Arguments for the MELD lock include protecting waitlist priority for terlipressin responders or partial responders who may miss offers due to MELD reduction in the terlipressin treatment window. Arguments against MELD lock include the fact that terlipressin may produce a durable response and improve overall survival and that equitable access to terlipressin is not guaranteed due to cost and availability. We subsequently discuss the proposed next steps for studying terlipressin implementation in the United States. A successful approach will require the involvement of all major stakeholders and the mobilization of our transplant community to spearhead research in this area.

A cost comparison of liver acquisition fees for donation after circulatory death versus donation after brain death donors.

Donation after circulatory death (DCD) donors now represent over 30% of the deceased donor pool in the United States. Compared to donation after brain death, DCD is less likely to result in transplantation. For each potential donor whose organs cannot be utilized for transplantation (ie, dry run), fees are associated with the attempted donation, which add to the overall costs of organ acquisition. To better characterize the true costs of DCD liver acquisition, we performed a cost comparison of the fees associated with organ acquisition for DCD versus donation after brain death at a single transplant institute that comprises 2 liver transplant centers. Cost, recipient, and transportation data for all cases, including fees associated with liver acquisition from July 1, 2019, to October 31, 2021, were collected. We found that the total cost of DCD liver acquisition per liver transplant was $15,029 more than that for donation after brain death donation, with 18% of the costs of the DCD transplant attributed to dry runs. Overall, the costs associated with DCD transplantation accounted for 34.5% of the total organ acquisition costs; however, DCD transplantation accounted for 30.3% of the transplantation volume. Because the expansion of DCD is essential to increasing the availability of liver grafts for transplantation, strategies need to be implemented to decrease the costs associated with dry runs, including using local recovery, transferring donors to hospitals close to transplant centers, and performing more prerecovery organ analysis. Moreover, these strategies are needed to ensure that financial disincentives to DCD procurement and utilization do not reverse the gains made by expanding the organ donor pool using machine perfusion technologies.

Increasing practice and acceptable outcomes of high-MELD living donor liver transplantation in the USA.

Recent deceased-donor allocation changes in the United States may have increased high-Model for End-Stage Liver Disease (MELD) living donor liver transplantation (LDLT); however, outcomes in these patients remain poorly defined. We aimed to examine the impact of the MELD score on LDLT outcomes. Using UNOS data (January 1, 2010-December 31, 2021), LDLT recipients were identified and stratified into low-MELD (<15), intermediate-MELD (15-24), and high-MELD (≥25) groups. We compared outcomes between MELD-stratified LDLT groups and between MELD-stratified LDLT and donation after brain death liver transplantation recipients. We used Kaplan-Meier analysis to compare graft survival rates and multivariable Cox proportional hazards modeling to identify factors associated with graft outcomes. Of 3558 LDLTs, 1605 (45.1%) were low-MELD, 1616 (45.4%) intermediate-MELD, and 337 (9.5%) high-MELD. Over the study period, the annual number of LDLTs increased from 282 to 569, and the proportion of high-MELD LDLTs increased from 3.9% to 7.7%. Graft survival was significantly higher in low-MELD versus high-MELD LDLT recipients (adjusted HR = 1.36, 95% CI: 1.03-1.79); however, 5-year survival exceeded 70.0% in both groups. We observed no significant difference in graft survival between high-MELD LDLT and high-MELD donation after brain death liver transplantation recipients (adjusted HR: 1.25, 95% CI:0.99-1.58), with a 5-year survival of 71.5% and 77.3%, respectively. Low LDLT center volume (<3 LDLTs/year) and recipient life support requirement were both associated with inferior graft outcomes among high-MELD LDLT recipients. While higher MELD scores confer graft failure risk in LDLT, high-MELD LDLT outcomes are acceptable with similar outcomes to MELD-stratified donation after brain death liver transplantation recipients. Future practice guidance should consider the expansion of LDLT recommendations to high-MELD recipients in centers with expertise to help reduce donor shortage.

Long-term outcomes (beyond 5 years) of liver transplant recipients-A transatlantic multicenter study.

The long-term (>5 y) outcomes following liver transplantation (LT) have not been extensively reported. The aim was to evaluate outcomes of LT recipients who have survived the first 5 years. A multicenter retrospective analysis of prospectively collected data from 3 high volume LT centers (Dallas-USA, Birmingham-UK, and Barcelona-Spain) was undertaken. All adult patients, who underwent LT since the inception of the program to December 31, 2010, and survived at least 5 years since their LT were included. Patient survival was the primary outcome. A total of 3682 patients who survived at least 5 years following LT (long-term survivors) were included. Overall, median age at LT was 52 years (IQR 44-58); 53.1% were males; and 84.6% were Caucasians. A total of 49.4% (n=1820) died during a follow-up period of 36,828 person-years (mean follow-up 10 y). A total of 80.2% (n=1460) of all deaths were premature deaths. Age-standardized all-cause mortality as compared to general population was 3 times higher for males and 5 times higher for females. On adjusted analysis, besides older recipients and older donors, predictors of long-term mortality were malignancy, cardiovascular disease, and dialysis. Implementation of strategies such as noninvasive cancer screening, minimizing immunosuppression, and intensive primary/secondary cardiovascular prevention could further improve survival.